期刊
CANCER LETTERS
卷 251, 期 1, 页码 146-157出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2006.11.013
关键词
TRAIL; DR5; c-FLIP(L); lexatumumab; metastasis; orthotopic; renal cell carcinoma
类别
资金
- NCI NIH HHS [P50CA101942] Funding Source: Medline
- NIDDK NIH HHS [DK64062] Funding Source: Medline
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL-agonist compounds have the potential of being excellent cancer therapeutic agents with minimal cytotoxicity. Here, we examine the efficacy of the TRAIL-receptor 2 agonist, lexatumumab (Human Genome Sciences, Inc., Rockville, MD), and identify molecular pathways that differentiate between lexatumuntab-sensitive and lexatumumab-resistance renal cancer cells. In an orthotopic metastatic mouse model, we first demonstrate that lexatumumab was effective in reducing the tumor burden of primary and metastatic lexatumumab-sensitive xenografts. We demonstrate that lexatumumab-sensitive cells were capable of triggering both the extrinsic and the intrinsic apoptotic pathways as demonstrated by caspase 8 and caspase 9 activations, respectively, after treatment with lexatumumab. In addition, expression of e-FLIP(L) protein, an important regulator of TRAIL-induced apoptosis, decreased, while expression of the TRAIL-receptor 2, DR5, increased. This study serves as a pre-clinical model for using TRAIL-like therapies for patients with advanced RCC. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
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